The goal of the proposed studies is to determine the antibacterial functions of tumor necrosis factor (TNF), interleukin-1s (IL-1),l and the interferons (IFN). Models of acute or chronic murine listeriosis will be employed to analyze the functions of these cytokines in host defense against a facultative intracellular pathogen. Pure preparations of murine cytokines will be administered prophylactically, or therapeutically to Listeria-infected mice to determine whether they enhance nonspecific resistance mechanisms, and/or specific T cell-mediated anti-Listeria immunity. The temporal appearance and quantities of cytokines produced in organs in response to infection will be measured, and roles for these Listeria-induced molecules in resistance will be established by determining whether the administration of specific anti-cytokine neutralizing antibodies results in an exacerbation of infection. It is anticipated that resident tissue macrophages and recruited bone marrow-derived macrophages that mediated Listeria destruction are probably major sources of Listeria- induced TNF, IL-1, IFNalpha and IFNbeta. In vitro studies will examine the listericidal actions of Kupffer cells and recruited macrophages following treatment with each of these cytokines. Other studies will examine whether the cytokines in question can function to either induce macrophage monokine synthesis, or prime macrophages for enhanced monokine production in response to Listeria ingestion. Because it has now been definitely established that Listeria multiplies in hepatocytes in vivo, studies will be undertaken to determine whether the aforementioned cytokines can render hepatocytes resistant to penetration or intracellular multiplication of Listeria. It will also be determined whether TNF, Listeria-sensitized T cells, or natural killer cells are capable of lysing Listeria-infected hepatocytes or fibroblasts. Other studies will examine whether cytokines can enhance the cytolytic activity of TNF, or host effector cells for Listeria-infected nonprofessional phagocytic cells.
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